Respiratory Viruses and

Treatment Failure in Children

With Asthma Exacerbation
Joanna Merckx, MD,​a,​b Francine M. Ducharme, MD,​c,​d Christine Martineau, PhD,​e,​f Roger Zemek, MD,​g,​h
Jocelyn Gravel, MD,​c Dominic Chalut, MD,​i Naveen Poonai, MD,​j Caroline Quach, MD, MSc,​b,​e,​k
for the Pediatric Emergency Research Canada (PERC) DOORWAY team

OBJECTIVES: Respiratory pathogens commonly trigger pediatric asthma exacerbations, but abstract
their impact on severity and treatment response remains unclear.
METHODS: We performed a secondary analysis of the Determinants of Oral Corticosteroid
Responsiveness in Wheezing Asthmatic Youth (DOORWAY) study, a prospective cohort
study of children (aged 1–17 years) presenting to the emergency department with moderate
or severe exacerbations. Nasopharyngeal specimens were analyzed by RT-PCR for 27
respiratory pathogens. We investigated the association between pathogens and both
exacerbation severity (assessed with the Pediatric Respiratory Assessment Measure) and
treatment failure (hospital admission, emergency department stay >8 hours, or relapse) of
a standardized severity-specific treatment. Logistic multivariate regressions were used to
estimate average marginal effects (absolute risks and risk differences [RD]).
RESULTS: Of 958 participants, 61.7% were positive for ≥1 pathogen (rhinovirus was the most
prevalent [29.4%]) and 16.9% experienced treatment failure. The presence of any pathogen
was not associated with higher baseline severity but with a higher risk of treatment failure
(20.7% vs 12.5%; RD = 8.2% [95% confidence interval: 3.3% to 13.1%]) compared to
the absence of a pathogen. Nonrhinovirus pathogens were associated with an increased
absolute risk (RD) of treatment failure by 13.1% (95% confidence interval: 6.4% to 19.8%),
specifically, by 8.8% for respiratory syncytial virus, 24.9% for influenza, and 34.1% for
parainfluenza.
CONCLUSIONS: Although respiratory pathogens were not associated with higher severity on
presentation, they were associated with increased treatment failure risk, particularly in
the presence of respiratory syncytial virus, influenza, and parainfluenza. This supports
influenza prevention in asthmatic children, consideration of pathogen identification on
presentation, and exploration of treatment intensification for infected patients at higher
risk of treatment failure.

aDivision of Infectious Diseases, Department of Pediatrics, iThe Montreal Children’s Hospital, McGill University,
Montreal, Quebec, Canada; bDepartment of Epidemiology, Biostatistics, and Occupational Health, McGill
University, Montreal, Quebec, Canada; Departments of cPediatrics and dSocial and Preventive Medicine, CHU
Sainte-Justine, University of Montreal, Quebec, Canada; kInfection Prevention and Control Unit, Division of
Infectious Disease and Medical Microbiology, CHU Sainte-Justine, Montreal, Quebec, Canada; eDepartment
of Microbiology, Infectious Disease, and Immunology, University of Montreal, Montreal, Quebec, Canada;
fLaboratoire de Santé Publique du Québec, Institut National de Santé Publique du Québec, Sainte-Anne-de-
Bellevue, Canada; gDepartment of Pediatrics and Emergency Medicine, University of Ottawa, Ottawa, Ontario,
Canada; hChildren’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; and jChildren’s
Hospital, London Health Sciences Centre, London, Ontario, Canada
WHAT’S KNOWN ON THIS SUBJECT: Viruses trigger the majority of asthma
exacerbations in children; however, there is a lack of adequately powered
high-quality studies that provide conclusive evidence on pathogen-specific
determinants on clinical relevant outcomes of asthma exacerbation.
WHAT THIS STUDY ADDS: In children with moderate/severe exacerbations,
viral detection is not associated with greater severity on presentation;
however, the presence of specific pathogens, namely respiratory syncytial
virus, influenza, and parainfluenza, identified children with worse
outcomes and presenting with insufficient response to standardized
corticosteroids and bronchodilator treatment.

To cite: Merckx J, Ducharme FM, Martineau C, et al.

Respiratory Viruses and Treatment Failure in Children With
Asthma Exacerbation. Pediatrics. 2018;142(1):e20174105

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PEDIATRICS Volume 142, number 1, July 2018:e20174105 ARTICLE
Exacerbations constitute the largest
burden of disease in children with
asthma, with 60% to 80% being
triggered by respiratory pathogens.‍1
The use of reverse transcriptase
polymerase chain reaction (RT-PCR)
has facilitated our understanding
of the epidemiology of respiratory
pathogens in this population,​‍2 with
a growing interest in rhinovirus,
the most frequently identified
virus during exacerbations.‍1
Some reports have suggested an
association between rhinovirus C
and severe asthma exacerbations
and hospitalizations.‍3,​4 Recently,
enterovirus D68 has also been
reported in outbreaks of severe
respiratory complications in
children with asthma.‍5 However,
influenza’s role in exacerbation
severity and health care use
remains controversial.‍6 In addition,
respiratory syncytial virus (RSV),
parainfluenza virus (PIV), and other
pathogens, including atypical bacteria
(such as Mycoplasma pneumoniae),
have been associated with
exacerbations,​‍7 but only researchers
of a limited number of studies have
investigated the impact of specific
pathogens on severity,​‍4 and none
have primarily addressed treatment
response.
Emergency department (ED)
management with inhaled
bronchodilators and systemic
corticosteroids‍8,​9‍ for moderate or
severe asthma exacerbations has
been shown to reduce the risk of
hospitalization.‍10 Ducharme et al‍11
investigated the determinants of
treatment failure in children with
moderate or severe exacerbations
presenting to the ED in the
Determinants of Oral Corticosteroid
Responsiveness in Wheezing
Asthmatic Youth (DOORWAY) study,
the largest cohort of its kind. The
detection of a respiratory virus
was associated with treatment
failure. However, pathogen-specific
effects were not investigated.
Quantifying the impact of specific
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2 MERCKX et al
respiratory pathogens may (1) guide
infection prevention interventions
in children with asthma, (2) focus
efforts on pathogen diagnosis at
ED presentation, and (3) identify
children at higher risk of treatment
failure in whom treatment
intensification may be considered.
In children presenting to the ED
with a moderate or severe asthma
exacerbation, our aims were to
ascertain the association between the
presence of a laboratory-confirmed
specific respiratory pathogen and
both the baseline exacerbation
severity and the risk of ED treatment
failure.
METHODS
This study is an ancillary study in
which we explore specific infectious
etiologies of the DOORWAY primary
objective‍11 and is a multicenter
prospective ethics-approved cohort
study of children with moderate
or severe asthma exacerbation
presenting to 1 of 5 EDs of the
Pediatric Emergency Research
Canada network between 2011 and
2013. Briefly, the original study
authors’ objective was to identify
determinants of ED management
failure after standardized therapy.
Children were eligible if they
were 1 to 17 years of age, had a
physician diagnosis of asthma
based on a previous episode with
airflow obstruction with response
to asthma medication, ≥3 wheezing
episodes (if <2 years of age),​‍12,​13
‍ or
previous diagnostic lung function
test results and a physician diagnosis
of moderate or severe exacerbation
using the validated 12-point pediatric
respiratory asthma measure (PRAM)
score‍14 on ED presentation. An
independent committee adjudicated
cases with diagnostic uncertainty.
Patients were excluded if there
was suspicion of bronchiolitis or
foreign body aspiration, another
chronic respiratory disorder,
or a contraindication to study
medication treatment. All children
received a standardized dose of oral
corticosteroids (2 mg/kg [1 mg/kg in
1 site] of prednisone or prednisolone,
or 0.3 mg/kg of dexamethasone)
and bronchodilator treatment with
salbutamol, and those with severe
exacerbations additionally received
ipratropium bromide. All eligible
DOORWAY participants with a valid
respiratory specimen were included
in this study.
Exposure: Respiratory Specimen
Testing
A nasopharyngeal aspirate or swab
(flocked swab; Copan Diagnostics,
Murrieta, CA) was systematically
procured within 1 hour of study
inclusion, placed in 3 mL of viral
transport media (Universal Transport
Medium; Copan Diagnostics), and
frozen at −80°C. Adenovirus (B, C,
and D), coronavirus (229E, HKU1,
NL63, and OC43), enterovirus (A, B, C,
and D), influenza (A and B), PIV (1, 2,
3, and 4), human metapneumovirus
(hMPV) (A and B), RSV (A and B),
and rhinovirus (A and B) were
investigated by using a validated
multiplex RT-PCR microarray
hybridization assay.‍15 Nucleic acids
from respiratory specimens were
also tested by using a commercial
multiplex polymerase chain
reaction (PCR) assay‍16 to identify
the atypical bacteria M pneumoniae,
Chlamydophila pneumoniae, and
Bordetella pertussis.
All specimens that tested positive in
the enterovirus and/or rhinovirus
probe on the microarray assay‍15
but were negative for type-specific
enterovirus or rhinovirus (n = 302)
and those that tested negative
in the enterovirus or rhinovirus
probe but were positive for 1 of
the enterovirus– or rhinovirus
type–specific probes (n = 20) were
further tested by using RT-PCR
and sequencing‍17 in which we
targeted the 5′ untranslated region
of rhinovirus A, B, and C and some
enteroviruses, including enterovirus
D68 (GenBank accession numbers:
MF978769 to MF979073). For
samples with undetermined results
by additional testing (n = 16), results
from the original microarray analysis
were used. Results were interpreted
blinded to the clinical outcome.
Exposure variables were as follows:
specimens that tested positive for
either a virus or atypical bacteria
were coded as “pathogen-positive.”
Coinfection was defined as the
presence of ≥2 pathogens compared
to a single pathogen and no pathogen.
Outcome Measures
The PRAM score on presentation
was used to determine the
baseline exacerbation severity and
was analyzed alternatively as a
continuous variable and as a binary
variable; a PRAM score of 4 to 7
indicated moderate exacerbation,
and 8 to 12 indicated severe
exacerbation.‍14 ED management
failure, which was also the primary
composite outcome in the DOORWAY
study,​‍11 was defined as hospital
admission for asthma, treatment
in the ED lasting 8 hours or more
after corticosteroid administration,
or return to the ED within 72 hours
of discharge leading to hospital
admission or prolonged ED stay.
Data Analysis
The prevalence of each respiratory
pathogen was described by using
frequency counts and proportions.
Pathogens with <10 positive
cases were aggregated. Covariates
identified in the literature were
explored as potential confounders,
mediators, and interaction terms.
A detailed description of covariates
can be found in the primary study.‍11
Briefly, covariates included in
the models were age in years
(continuous), sex, child atopy
(based on parental report of a
diagnosis or symptoms of allergic
rhinitis and eczema as documented
by the International Study of
Asthma and Allergies in Childhood
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PEDIATRICS Volume 142, number 1, July 2018
questionnaire),​‍18 asthma phenotype
(intermittent or persistent), oral
corticosteroid use in the preceding
12 months as a marker of morbidity,
asthma control (measured with the
6-point Asthma Quiz for Kidz),​‍19
asthma controller use (daily, only
when sick, or none), season (based
on the calendar), upper respiratory
tract infection (URTI) at index visit
(clinical diagnosis), fever (at ED
presentation), pneumonia (physician
diagnosis based on clinical signs with
chest radiograph), tobacco exposure
(categorical variable based on saliva
cotinine levels sampled after study
inclusion), average family income
quantile (based on postal code census
data as a proxy for socioeconomic
characteristics), and study site.
Potential interactions between
exposures and atopy, allergic rhinitis,
income, and the possible mediators
(fever, pneumonia, and URTI) were
assessed on the additive scale. Linear
and logistic regressions were used
to investigate the association with
exacerbation severity by using the
baseline PRAM as a continuous or
dichotomous outcome, respectively,
and logistic regression for association
with treatment failure. This resulted
in 1 model in which the exposure
was any pathogen versus no
pathogen, 1 model for rhinovirus-
positive versus non–rhinovirus-
positive versus pathogen-negative,
8 models for each specific pathogen
exposure (rhinovirus A, B, and C;
RSV; influenza; hMPV; PIV; and
enterovirus D68 as the categorical
variable versus “any other pathogen–
positive” versus pathogen-negative)
in which pathogen-negative was used
as the reference, and 1 final model
used to compare coinfection (>1
pathogen) versus single pathogen.
Results of regression models are
presented as predicted probabilities
of the outcome (absolute risks [ARs]
and risk differences [RDs] with their
95% confidence intervals [CIs]) and
represent the average marginal effect
across the total study population.‍20–‍ 22
‍ markedly (‍Fig 2).
Patients with missing data for
variables included in these models
were excluded from the analysis.
Model fit was assessed with the area
under the curve for logistic (and with
R-squared for linear) regression. No
correction for multiple testing was
applied.‍23 Analyses were performed
by using Stata 13 (Stata Corp, College
Station, TX) and R version 3.2.1
(www.​r-​project.​org).
RESULTS
Of 1012 participants enrolled in
the DOORWAY study, 958 children
were included in our assessment
of association with exacerbation
severity, and 924 had ED treatment
failure (‍Fig 1).
Distribution of Respiratory
Pathogens: Patient and Exacerbation
Characteristics
Of the 958 respiratory specimens
tested, 591 (61.7%) were positive
for ≥1 pathogen, with coinfection
present in 81 specimens (8.5%);
RSV and coronavirus were the most
frequent copathogens (n = 13).
The most prevalent pathogen was
rhinovirus (n = 282; 29.4%), and
rhinovirus C was the most frequent
species (n = 174; 18.2%), followed by
RSV (n = 171; 17.9%). M pneumoniae
was identified in only 2 patients
(‍Table 1).
Compared to those without, children
with a laboratory-confirmed
pathogen were younger (median
[interquartile range (IQR)] age: 2
[1–5] vs 4 [2–7] years), had higher
tobacco exposure (cotinine levels ≥4
ng/mL in 6.8% vs 3.8%), and were
slightly more likely to present with
fever (29.4% vs 24.2%). Compared
to children who were not rhinovirus-
positive, children with rhinovirus
were less often febrile (16.2% vs
41.2%) and less frequently diagnosed
with pneumonia (5.0% vs 15.9%;
‍Table 2). The seasonal distribution of
specific respiratory viruses differed
3

FIGURE 1
Flowchart of patient selection from the DOORWAY study.
Association Between Pathogen
and Exacerbation Severity on
Presentation
The proportion of children presenting
with a severe exacerbation was 33.3%
(95% CI: 30.3% to 36.3%). By using
the initial triage PRAM score as a
binary outcome (moderate versus
severe exacerbation), no positive
association was found between the
presence of any pathogen and severe
versus moderate exacerbation.
The adjusted AR of a severe
exacerbation was 32.4% (95% CI:
29.0% to 35.8%) in the presence
of a pathogen and 38.3% (95% CI:
33.6% to 43.0%) in the absence of
a pathogen, representing an RD of
−5.8% (95% CI: −11.8 to 0.01; ‍Fig 3A,
Supplemental Table 3, Supplemental
Fig 5). Although the risk of severe
exacerbation in rhinovirus-positive
children was similar to that in those
with no pathogen, the presence
of a nonrhinovirus pathogen was
associated with a 12.9 percentage
point–lower (95% CI: −19.5% to
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4 MERCKX et al
−6.3%) adjusted risk of severe
exacerbation compared with no
pathogen. The presence of hMPV and
PIV were associated with a lower
risk of severe asthma with adjusted
RDs (95% CI) of −13.6% (−23.0%
to −4.3%) and −31.7% (−44.5% to
−18.9%), respectively. No statistically
significant association was found
between severity and RSV, influenza,
enterovirus D68, adenovirus, and
coronavirus (‍Fig 3B, Supplemental
Table 3, Supplemental Fig 5). The
pathogen-specific risk did not change
when stratifying for coinfection.
The association between exposure
and severity was also investigated
by using the PRAM score as a
continuous outcome and repeating the
exposure models; they confirmed the
conclusion of all results using PRAM
as a dichotomous outcome.
Association Between Pathogen and
Treatment Failure
Overall, 156 of 924 participants
(16.9%; 95% CI: 14.5% to 19.3%)
experienced treatment failure. The
presence of any respiratory pathogen
(AR = 20.7%; 95% CI: 17.4% to
24.1%) compared to no pathogen
(AR = 12.5%; 95% CI: 9.0% to 16.0%)
was associated with an increased
risk of treatment failure (RD = 8.2%;
95% CI: 3.3% to 13.1%; ‍Fig 4A,
Supplemental Table 3, Supplemental
Fig 6). Although the presence of
rhinovirus and its species was not
associated with treatment failure,
there was a higher risk of failure
in children with a nonrhinovirus
infection (AR = 25.4%; 95% CI:
19.8% to 31.0%) compared to those
with no pathogen present, resulting
in an adjusted RD of 13.1% (95% CI:
6.4% to 19.8%).
More specifically, RSV, influenza, and
PIV were associated with a higher
risk of treatment failure: 21.4% (95%
CI: 14.1% to 28.7%), 37.5% (95% CI:
17.8% to 57.2%), and 46.7% (95%
CI: 20.4% to 73.0%), respectively.
This resulted in AR increases of
8.8% (95% CI: 0.4% to 17.2%),
24.9% (95% CI: 4.7% to 45.1%), and
34.1% (95% CI: 7.5% to 60.7%; ‍Fig
4B), respectively. hMPV had an RD
of 8.0% (95% CI: −1.6% to 17.6%).
Coronavirus, adenovirus, enterovirus
D68, and the presence of a
coinfection were not associated with
an increased risk of failure (‍Fig 4B,
Supplemental Table 3, Supplemental
Fig 6). Pathogen-specific risk did
not change when stratifying for the
presence of a coinfection.
DISCUSSION
In this large cohort, approximately
two-thirds of children presenting
to the ED with moderate or severe
asthma exacerbation had a positive
respiratory specimen result for
1 or more respiratory viruses or,
rarely, atypical bacteria. No positive
association was found between
the presence of any pathogen
and exacerbation severity on
presentation. In fact, some viruses
were associated with a significantly
lower severity. Despite standardized
TABLE 1 Results of Multiplex PCR Testing of Nasopharyngeal Aspirate Specimens forefront as a potential cause for
Respiratory Pathogen Identified N = 958, n (%) more severe disease.‍4 We confirmed
Respiratory pathogena 591 (61.7)
its high prevalence but were unable
  Virus 590 (61.6) to confirm an increased severity
  Atypical bacteriab 2 (0.2) or greater treatment failure in
No. pathogensc rhinovirus- or rhinovirus C–infected
  0 367 (38.3)
children. Perhaps rhinovirus plays a
  1 510 (53.3)
  2 68 (7.1) role in the initiation of exacerbations
  3 13 (1.4) that are severe enough to warrant
health care contact, but once infected,
Specific pathogens response to treatment appears
  Rhinovirus (any) 282 (29.4)
favorable. This is in line with a
  A 97 (10.1)
  B 11 (1.2) subgroup analysis of a randomized
  C 174 (18.2) controlled trial of children treated
  Enterovirus (any) 31 (3.2) with corticosteroids in which those
  A 1 (0.1) with rhinovirus responded better
  B 2 (0.2)
to steroid treatment than those
  C 3 (0.3)
  D68 25 (2.6) who tested negative for entero/
  Nontyped enterovirus and/or rhinovirus 14 (1.5) rhinovirus.‍24

Other (nonenterovirus or rhinovirus) In contrast, the presence of

  RSV (any) 171 (17.9)
nonrhinovirus pathogens as a group,
  A 126 (13.2)
  B 46 (4.8) and particularly hMPV and PIV, was
  hMPV (any) 96 (10.0) associated with a larger proportion of
  A 46 (4.8) children presenting with a moderate,
  B 53 (5.5) rather than severe, exacerbation;
  Influenza virus (any) 24 (2.5)
however, nonrhinovirus pathogens
  A 17 (1.8)
  B 7 (0.7) were significantly linked to higher
  Adenovirus (any) 12 (1.3) treatment failure, particularly
  A 2 (0.2) with RSV, influenza, and PIV, even
  B 0 (0) after adjustment for patient and
  C 10 (1.0)
exacerbation characteristics. Indeed,
  E 0 (0)
  PIV (any) 14 (1.5) in this group of children aged at least
  1 0 1 year in whom bronchiolitis was
  2 0 specifically excluded, we observed a
  3 10 (1.0) significant association between RSV
  4 4 (0.4)
and increased treatment failure by
  Coronavirus (any) 33 (3.4)
  OC43 16 (1.7) an absolute 8%. This observation is
  HKU1 6 (0.6) in line with a small study in which
  229E 3 (0.3) researchers documented a lower
  NL63 10 (1.0) response to steroids in children with
a Viral pathogen or atypical bacteria. asthma who were infected with RSV
b Total of 952 specimens.
c Viral and atypical bacteria.
compared to those who were not
infected.‍25 It is also congruent with
substantive literature on the lack
therapy with corticosteroids dimensions of the impact of viral of response to corticosteroids and
and severity-specific inhaled infections in children with acute bronchodilators in children with RSV
bronchodilators, the presence of asthma. bronchiolitis,​‍26,​27
‍ which raises the
any respiratory pathogen (and more possibility that RSV per se confers
specifically, of a nonrhinovirus The high prevalence of rhinovirus treatment resistance irrespective of
pathogen) was associated with more C in children presenting with disease and not only in infants aged
treatment failure compared with asthma exacerbation, its presumed <1 year with wheezing.‍28 The third
noninfected counterparts. Severity association with asthma-related most frequent organism, hMPV, was
on presentation and response to hospitalization, and its peak in the associated with a risk of treatment
treatment thus appear as 2 distinct fall have brought this virus to the failure similar to that of RSV, but its RD

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PEDIATRICS Volume 142, number 1, July 2018 5
6
TABLE 2 Baseline Patient Characteristics
Variable Total Patients Respiratory Respiratory Rhinovirus-Positive (n = 282) Non–Rhinovirus-Positive (n = 309) Coinfection
(n = 958),​a Pathogen–Positive (n Pathogen–Negative
Total, N (%) Rhinovirus Rhinovirus Rhinovirus Total, N Enterovirus RSV hMPV Influenza PIV (n Single Pathogen Coinfection
N (%) = 591),​b N (%) (n = 367), N (%)
A (n = 97), B (n = 11), C (n = 174), (%) D68 (n = 25), (n = 171), (n = 96), (n = 24), N = 14), (n = 510), (n = 81),
N (%) N (%) N (%) N (%) N (%) N (%) (%) N (%) N (%) N (%)
Age (n = 957; 0.1% missing)
Median (IQR) 3 (2–6) 2 (1–5) 4 (2–7) 3 (1–5) 3 (2–5) 8 (2–12) 2 (1–5) 2 (1–4) 3 (1–5) 2 (1–3) 2.5 (1–5) 3.5 (2–7) 2 (1–2) 2 (1–5) 2 (1–4)
Male sex 635 (66.3) 393 (66.5) 242 (65.9) 197 (69.9) 73 (75.3) 5 (45.5) 119 (68.4) 196 (63.4) 15 (60) 111 (64.91) 61 (63.5) 14 (58.3) 9 (64.3) 331 (64.9) 62 (76.54)
Risk factors for exacerbation
  Atopy 666/957 (69.6) 413 (69.9) 253 (69.1) 189 (67.0) 64 (66.0) 7 (63.6) 118 (67.8) 224 (72.5) 19 (76.0) 123 (71.9) 68 (70.8) 13 (54.2) 9 (64.3) 366 (71.8) 47 (58.0)
(0.1%
missing)
  Tobacco exposure (0.3% missing)
  Cotinine level ≥4 54/955 (5.7) 40 (6.8) 14 (3.8) 20 (7.1) 4 (4.2) 1 (9.1) 15 (8.7) 20 (6.5) 0 (0) 18 (10.53) 4 (4.2) 2 (8.3) 0 (0) 35 (6.9) 5 (6.2)
ng/mL
  Cotinine level 1–4 252/955 (26.4) 156 (26.5) 96 (26.2) 67 (23.9) 29 (30.2) 1 (9.1) 37 (21.4) 89 (28.9) 8 (33.3) 38 (22.22) 27 (28.1) 9 (37.5) 2 (14.3) 137 (27.0) 19 (23.5)
ng/mL
  Cotinine level <1 649/955 (68.0) 392 (66.7) 257 (70.0) 193 (68.9) 63 (65.6) 9 (81.8) 121 (69.9) 199 (64.6) 16 (66.7) 115 (67.25) 65 (67.7) 13 (54.2) 12 (85.7) 335 (66) 57 (70.4)
ng/mL per d
Asthma phenotype (n = 957; 0.1% missing)
  Intermittent 731 (76.4) 450 (76.4) 281 (76.8) 221 (78.14) 71 (73.2) 7 (63.6) 143 (82.2) 229 (74.1) 19 (76.0) 130 (76.0) 69 (71.9) 18 (75.0) 10 (71.4) 393 (77.1) 57 (70.4)
asthma
  Persistent asthma 226 (23.6) 141 (23.9) 85 (23.2) 61 (21.6) 26 (26.8) 4 (36.4) 31 (17.8) 80 (25.9) 6 (24.0) 41 (24.0) 27 (28.1) 6 (25.0) 4 (28.6) 117 (22.9) 24 (29.6)
Morbidity before enrollment
  Patients with ≥1 475/952 (46.9) 275 (46.9) 192 (52.6) 140 (49.7) 49 (50.5) 3 (27.3) 88 (50.6) 135 (44.3) 9 (36.0) 73 (43.2) 41 (43.1) 9 (37.5) 10 (71.4) 243 (48.0) 32 (39.5)
course of oral (0.6%
corticosteroids in missing)
previous y
  Patient with 146/957 (15.3) 96 (16.2) 50 (13.7) 48 (17.0) 16 (16.5) 0 (0) 32 (18.4) 48 (15.5) 4 (16.0) 24 (14.04) 8 (8.3) 5 (20.8) 4 (28.6) 87 (17.1) 9 (11.1)
≥1 hospital (0.1%
admission in missing)
previous y
  Asthma quiz for 3 (2–4) (n = 3 (2–4) 3 (2–4.5) 3 (2–4) 4 (2–5) 3 (2–5) 3 (1–4) 4 (2–5) 3 (1.5–3.5) 4 (2–4) 4 (3–5) 4 (2–5) 4 (2–5) 3 (2–5) 3.5 (2–4)
kids score, 938, 2.1%
median (IQR) missing)
Prescribed asthma controller
403 (42.1) 254 (43.0) 149 (40.6) 122 (43.7) 40 (41.2) 6 (54.6) 76 (43.7) 132 (40.6) 14 (56.0) 85 (49.7) 36 (37.5) 8 (33.3) 4 (28.6) 215 (42.2) 39 (48.1)

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  None
  Daily maintenance 279 (29.1) 175 (29.6) 104 (28.3) 84 (29.8) 29 (30.0) 0 (0) 55 (31.6) 91 (29.5) 5 (20.0) 44 (25.7) 30 (31.3) 11 (45.8) 6 (42.9) 151 (29.6) 24 (29.6)
  Episodic intake 276 (28.8) 162 (27.4) 114 (31.1) 76 (27.0) 28 (28.9) 5 (45.5) 43 (24.7) 86 (27.8) 6 (24.0) 42 (24.6) 30 (31.3) 5 (20.8) 4 (28.6) 144 (28.2) 18 (22.2)
(when sick)
Season
  Spring 225 (23.5) 128 (21.7) 97 (26.4) 79 (28.0) 47 (48.5) 1 (9.1) 31 (17.8) 49 (15.9) 0 (0) 25 (14.6) 23 (24.0) 5 (20.8) 3 (21.4) 108 (21.2) 20 (24.7)
  Summer 85 (8.9) 61 (10.3) 24 (6.5) 39 (13.8) 12 (12.4) 1 (9.1) 26 (14.9) 22 (7.1) 8 (32.0) 11 (6.4) 13 (5) 0 (0) 1 (7.1) 50 (9.8) 11 (13.6)
  Fall 369 (38.5) 201 (34.0) 168 (45.8) 124 (44.0) 28 (28.9) 9 (81.8) 87 (50.0) 77 (24.9) 17 (68.0) 33 (19.3) 18 (18.8) 3 (12.5) 5 (35.7) 186 (36.5) 15 (18.5)
  Winter 279 (29.1) 201 (34.0) 78 (21.3) 40 (14.2) 10 (10.31) 0 (0) 30 (17.2) 161 (52.1) 0 (0) 102 (59.7) 42 (43.8) 16 (66.7) 5 (35.7) 166 (32.6) 35 (43.2)
Symptoms of infection
  Fever present 260/949 (27.4) 172 (29.4) 88 (24.2) 45 (16.2) 15 (15.6) 1 (9.1) 29 (17.0) 127 (41.2) 4 (16.7) 76 (44.7) 41 (43.1) 13 (54.2) 1 (7.1) 141 (27.9) 31 (38.8)
(0.9%
missing)

MERCKX et al
 Coinfection did not reach statistical significance.

48 (59.3)
10 (12.4)

14 (17.3)

20 (24.7)

55 (67.9)

33 (40.7)
(n = 81),
Although involved in recent outbreaks

3 (3.7)
3 (3.7)
N (%)
of severe respiratory infections,​5
Coinfection

enterovirus D68 was not associated

Single Pathogen

with more severe exacerbations or

339 (66.5)
102 (20.0)

162 (31.8)

236 (46.3)

171 (33.5)
(n = 510),

74 (14.5)
53 (10.4)

38 (7.5)
excess treatment failure in our cohort
N (%)

perhaps because of differences in

subtypes related to the more recent

14 (58.3) 13 (92.9)
3 (12.5) 3 (21.4)
5 (35.7)

7 (29.2) 3 (21.4)

14 (58.3) 8 (57.1)
outbreaks. Although previously

1 (7.1)
Influenza PIV (n
(n = 96), (n = 24), N = 14),
N (%)
0 (0)

0 (0)
associated with severe infection and
lower respiratory tract symptoms

10 (41.7)
3 (12.5)

5 (20.8)

0 (0)
(%)

in patients with asthma,​‍29 our few

Non–Rhinovirus-Positive (n = 309)

cases of PIV 3 specifically and PIV in

108 (63.2) 64 (66.7)

32 (33.3)
16 (16.7)

15 (15.6)

17 (17.7)

66 (68.8)
7 (7.3)
6 (6.3)

general were insufficient to firmly

hMPV

N (%)

conclude on the effect on severity.

Finally, the few children who tested
D68 (n = 25), (n = 171),

63 (36.8)
33 (19.3)

35 (20.5)

45 (26.3)

99 (57.9)
16 (9.4)
11 (6.4)
N (%)
RSV

positive for influenza or PIV (n = 24

and n =14, respectively) had a striking
Total, N (%) Rhinovirus Rhinovirus Rhinovirus Total, N Enterovirus

≥20% AR of treatment failure than

16 (64.0)
11 (44.0)

9 (36.0)
3 (12.0)

9 (36.0)
3 (12.0)
2 (8.0)

2 (8.0)
N (%)

pathogen-negative patients. Although

this may explain the reported excess
118 (67.8) 209 (67.6)

56 (32.2) 100 (32.4)

62 (35.6) 175 (56.6)
49 (15.9)

55 (17.8)

71 (40.8) 78 (25.2)
32 (18.4) 36 (11.7)
20 (6.5)

hospitalizations for cardiopulmonary

(%)

disease in children with asthma that

is associated with influenza,​‍30 asthma
A (n = 97), B (n = 11), C (n = 174),

39 (22.4)
9 (5.2)

9 (5.2)
N (%)

was not identified as a risk factor for

influenza-related hospitalization in
Rhinovirus-Positive (n = 282)

a large meta-analysis.‍6 Nevertheless,

7 (63.6)

4 (36.4)
2 (18.2)

3 (27.3)

3 (27.3)
6 (54.6)
1 (9.1)
1 (9.1)
N (%)

response to therapy is significantly

reduced with RSV, influenza, and PIV.
53 (54.6)

44 (45.4)
19 (19.8)

32 (32.9)

48 (49.5)
3 (3.1)

8 (8.3)
9 (9.3)
N (%)

Only a limited number of patients

were found positive for atypical
bacteria, compared to previous
116 (41.1)

178 (63.1)

104 (36.9)
104 (36.9
61 (21.7)

41 (14.5)
14 (5.0)

21 (7.5)

studies.‍7 The use of nasopharyngeal

or nasal swabs instead of throat
b Positive for at least 1 of the RT-PCR–investigated viral pathogens or M pneumoniae–positive.

swabs might have accounted for

Pathogen–Negative
(n = 367), N (%)
Respiratory

the lower sensitivity of our tests.‍31

135 (36.8)

252 (68.7)

115 (31.3)
62 (16.9)

99 (27.0)
97 (26.4)
36 (9.81)
24 (6.5)

Moreover, there was no association

between coinfection and less
favorable outcomes perhaps because
the species is more important than
Pathogen–Positive (n

the number of pathogens.

= 591),​b N (%)
Respiratory

387 (65.5)

204 (34.5)
116 (19.7)

182 (30.8)

291 (49.2)
63 (10.7)

77 (13.0)
41 (6.9)

What are the implications of these

findings? Perhaps treatment
intensification with inhaled
anticholinergics or magnesium sulfate,
178/957 (18.6)
Total Patients

both of which reduce acetylcholine

87/957 (9.1)

missing)

missing)
(n = 958),​a

319 (33.3)
281 (29.3)
174 (18.2)

426 (44.5)

639 (66.7)
(0.1%

(0.1%

77 (8.0)
N (%)

Shown are overall and by pathogen.

release at the myoneural junction,

could block the vagal-mediated
PRAM score on presentation

a Unless otherwise stated.

reflex bronchoconstriction observed

TABLE 2  Continued

in viral-induced exacerbation.‍32
  PRAM score 8–12
  PRAM score 4–8
  URTI symptoms

(moderate)

These therapies that are currently

(severe)
  Pneumonia

reserved for severe exacerbations

Study site
Variable

may be tested for their efficacy in

  1
  2
  3
  4

exacerbations of any severity triggered

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PEDIATRICS Volume 142, number 1, July 2018 7

FIGURE 2
Seasonal distribution of all 25 respiratory viruses identified in 958 specimens, representing species
for rhinovirus (A, B, and C) and enterovirus (D68) and aggregated groups for the remainder (a total
of 10 exposures); 80 specimens were positive for >1 respiratory virus.
by RSV, influenza, and PIV, which
have been associated with poor
treatment response. Although the
mechanism of action remains to be
clarified, azithromycin,​‍33 which has
been shown effective in preschoolers
with previously severe exacerbations,
could be explored as an alternative
pathogen-nonspecific therapy to
target antineutrophilic inflammation.
Clearly, any pathogen-specific antiviral
and/or treatment intensification first
requires an identification of pathogens
associated with each exacerbation;
this would imply real-time diagnostic
test in the ED by using RT-PCR or
a wider introduction of point-of-
care testing. Until then, preventive
measures should be prioritized. This
is particularly important in light of
the growing knowledge that early-
life RSV and rhinovirus infections
are also associated with an increased
risk of inception of asthma‍34 and,
for the former, poorer ED treatment
response. Children with asthma should
remain a priority group for influenza
immunization because of the newly
established association between
influenza and ED management failure
combined with well-recognized
influenza-related complications.
Although this recommendation has
been challenged by a 2013 Cochrane
review, in which researchers failed to
find clear evidence that immunization
reduced the occurrence and severity
of influenza-associated asthma, Cates
et al‍35 underlined the paucity of
efficacy trials contributing data to their
meta-analysis. Given the documented
safety of influenza immunization
in children with asthma and its
expected protective effect, it appears
reasonable to pursue strategies to
improve immunization coverage for
influenza and invest in efforts for the
development of vaccines for RSV and
rhinovirus.
We acknowledge the following
limitations. Although our study
is the largest cohort of its kind,
with a richness of data that made
it possible to adjust for important
patient characteristics, children
presenting with a mild exacerbation
were excluded, thus limiting
our ability to identify a potential
differential impact of pathogens on
the full range of asthma exacerbation
severity. Although we tested for

FIGURE 3
Association between respiratory pathogens and the severity of exacerbation at presentation. Average marginal effects are presented with adjusted RDs of
severe exacerbation from multivariate logistic regressions. The reference used for RDs was the pathogen-negative category for each given model except
for coinfection, for which the reference used was pathogen-positive for a single pathogen. A, Average RDs of severe exacerbation by pathogen. B, Average
RDs of severe exacerbation by pathogen.

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8 MERCKX et al
FIGURE 4
Association between respiratory pathogens and ED treatment failure. Average marginal effects are presented with adjusted RDs of ED treatment failure
from multivariate logistic regressions. a The reference used for RDs was the pathogen-negative category for each given model except for coinfection, for
which the reference used was “pathogen-positive for a single pathogen.” Rhinovirus-positive and non–rhinovirus-positive test for interaction had a P
value result of .0499. A, Average RDs of failure of ED treatment by pathogen. B, Average RDs of failure of ED treatment by specific pathogen.
27 respiratory (including new)
pathogens, microorganisms identified
by PCR could have included both
nonreplicating viruses and colonizing
microorganisms. Thus, we cannot
rule out that some episodes may
not have been triggered by the
identified respiratory pathogen. Such
misclassification may lead to some
inaccuracies; however, it should
be nondifferential and would have
biased our results toward the null.
Yet, because most parents reported
that the index episode was triggered
by a URTI, it is more likely than not
that the identified microorganism was
associated with symptoms. Because
atopy was assessed by parental report
and their recall of allergy testing, with
no systematic testing with serum-
specific immunoglobulin E or allergy
testing, our ability to investigate
the interaction between pathogen
and atopy as observed in some
studies‍36 was suboptimal. Moreover,
recent exposure to allergens‍37 was
not documented. Finally, the use of
anticholinergics was severity-specific,
and because it differed between
children with moderate and severe
exacerbations, it may have interacted
with some viruses to improve
treatment response and reduce our
ability to identify poor responders.
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PEDIATRICS Volume 142, number 1, July 2018
CONCLUSIONS de Laval. We also thank the following
In children presenting to the ED contributing PERC (Pediatric
with a moderate or severe asthma Emergency Research Canada) team
exacerbation, no virus, including members: Samina Ali, Mari-Christine
the most prevalent organism Auclair, Andrew Dixon, Rebecca
(rhinovirus C), was associated Emerton, Stephen Freedman,
with higher exacerbation severity. Amanda Newton, Amy Plint, Caitlin
In fact, nonrhinovirus pathogens Prendergast, and Antonia Stang.
were associated with less severe
exacerbations but with more ED
treatment failure; RSV, influenza,
and PIV increased by 8% to ABBREVIATIONS
34% the AR of treatment failure. AR: absolute risk
Interventions for RSV prevention and CI: confidence interval
influenza immunization thus need DOORWAY: Determinants of Oral
to be revisited. The efficacy of both Corticosteroid
pathogen-specific and nonspecific Responsiveness in
therapies should be further explored Wheezing Asthmatic
to decrease the risk of treatment Youth
failure in children with acute ED: emergency department
asthma by using advanced and rapid hMPV: human metapneumovirus
pathogen identification in the ED to IQR: interquartile range
enable their implementation. PCR: polymerase chain reaction
PIV: parainfluenza virus
ACKNOWLEDGMENTS PRAM: pediatric respiratory
asthma measure
We acknowledge the support of
RD: risk difference
the Fonds de la Recherche en Santé
RSV: respiratory syncytial virus
du Québec for the infrastructure
RT-PCR: reverse transcriptase
support provided to the Research
polymerase chain
Institutes of the Centre Hospitalier
reaction
Universitaire Sainte-Justine, the
URTI: upper respiratory tract
McGill University Health Centre, and
infection
the Centre Hospitalier Universitaire
9
Dr Merckx conceptualized the data analysis, conducted the analysis and presentation of results, and wrote the manuscript; Dr Ducharme provided the primary
study data, protocol, and statistical analysis from the primary study, provided feedback on the analysis protocol, interpretation of results, and feedback on
manuscript revisions, and revised the final version; Dr Quach led the laboratory analysis of the respiratory specimens, supervised the data analysis plan,
statistical analysis, and manuscript writing, provided feedback on the interpretation of results and manuscript revisions and funding for the substudy, and
revised the final version; Drs Martineau, Zemek, Gravel, Chalut, and Poonai provided feedback on manuscript revisions and revised the final version; and all
authors approved the final manuscript as submitted.
This trial has been registered at www.​clinicaltrials.​gov (identifier NCT02013076).
DOI: https://​doi.​org/​10.​1542/​peds.​2017-​4105
Accepted for publication Apr 3, 2018
Address correspondence to Caroline Quach, MD, MSc, Infection Prevention and Control Unit, CHU Sainte-Justine, 3175 Cote Sainte-Catherine, Montreal, QC H3T 1C5,
Canada. E-mail: c.quach@umontreal.ca
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2018 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: Dr Quach was supported through an external salary award (Fonds de recherche du Québec – Santé (FRQ-S) senior, grant 26873); the
other authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by the Canadian Institutes of Health Research (grant 102547) under the title “Determinants of Oral Corticosteroid Responsiveness in
Wheezing Asthmatic Youth.” Additional testing was supported by internal funds.
POTENTIAL CONFLICT OF INTEREST: Dr Ducharme received unrestricted donations from Boehringer Ingelheim, Merck Canada, GlaxoSmithKline, and Novartis and
a research grant from Merck and is serving on an advisory board of Boehringer Ingelheim, Sanofi Regeneron, and AstraZeneca unrelated to the current study. Dr
Quach has received funding from Sage Products LLC and AbbVie for research grants unrelated to the current study; the other authors have indicated they have
no potential conflicts of interest to disclose.

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 Respiratory Viruses and Treatment Failure in Children With Asthma
Exacerbation
Joanna Merckx, Francine M. Ducharme, Christine Martineau, Roger Zemek, Jocelyn
Gravel, Dominic Chalut, Naveen Poonai, Caroline Quach and for the Pediatric
Emergency Research Canada (PERC) DOORWAY team
Pediatrics 2018;142;
DOI: 10.1542/peds.2017-4105 originally published online June 4, 2018;

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 Respiratory Viruses and Treatment Failure in Children With Asthma
Exacerbation
Joanna Merckx, Francine M. Ducharme, Christine Martineau, Roger Zemek, Jocelyn
Gravel, Dominic Chalut, Naveen Poonai, Caroline Quach and for the Pediatric
Emergency Research Canada (PERC) DOORWAY team
Pediatrics 2018;142;
DOI: 10.1542/peds.2017-4105 originally published online June 4, 2018;

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